Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

News from NHLBI: Nutrition Research at the National Heart, Lung, and Blood Institute and Future Opportunities.

BACKGROUND: Nutrition plays a major role in the prevention and treatment of cardiovascular and other chronic diseases; hence, nutrition research is a priority for the National Heart, Lung, and Blood Institute (NHLBI). The purpose of this analysis is to describe the scope of NHLBI-funded extramural nutrition research grants over the past decade and offer insights into future opportunities for nutrition research relevant to NHLBI's mission. METHODS: Data were extracted using the Research, Condition, and Disease Categorization spending categories from the publicly available NIH Research Portfolio Online Reporting Tool Expenditures and Results. New 2018 and 2019 grants were coded into categories and mapped to the 2016 NHLBI Strategic Vision priorities. RESULTS: Approximately 90% of nutrition research funds supported extramural grants, particularly through investigator-initiated R series grants (69.6%). Of these, 19.8% were classified as clinical trials. Consistent nutrition-related topics, including physical activity, weight loss, fatty acids, metabolic syndrome, childhood obesity, and other topics such as gut microbiota, arterial stiffness, sleep duration, and meal timing, emerged in 2014-2019.  Mapping of the NHLBI Strategic Vision objectives revealed that 32% of newly funded grants focused on pathobiological mechanisms important to the onset and progression of heart, lung, blood, and sleep disorders, with opportunities including developing novel diagnostic and therapeutic strategies and clinical and implementation science research. DISCUSSION: The findings show the breadth of NHLBI-funded nutrition research and highlight potential research opportunities for nutrition scientists.

Harmonization of Respiratory Data From 9 US Population-Based Cohorts: The NHLBI Pooled Cohorts Study.

Chronic lower respiratory diseases (CLRDs) are the fourth leading cause of death in the United States. To support investigations into CLRD risk determinants and new approaches to primary prevention, we aimed to harmonize and pool respiratory data from US general population-based cohorts. Data were obtained from prospective cohorts that performed prebronchodilator spirometry and were harmonized following 2005 ATS/ERS standards. In cohorts conducting follow-up for noncardiovascular events, CLRD events were defined as hospitalizations/deaths adjudicated as CLRD-related or assigned relevant administrative codes. Coding and variable names were applied uniformly. The pooled sample included 65,251 adults in 9 cohorts followed-up for CLRD-related mortality over 653,380 person-years during 1983-2016. Average baseline age was 52 years; 56% were female; 49% were never-smokers; and racial/ethnic composition was 44% white, 22% black, 28% Hispanic/Latino, and 5% American Indian. Over 96% had complete data on smoking, clinical CLRD diagnoses, and dyspnea. After excluding invalid spirometry examinations (13%), there were 105,696 valid examinations (median, 2 per participant). Of 29,351 participants followed for CLRD hospitalizations, median follow-up was 14 years; only 5% were lost to follow-up at 10 years. The NHLBI Pooled Cohorts Study provides a harmonization standard applied to a large, US population-based sample that may be used to advance epidemiologic research on CLRD.

Planning for the future workforce in hematology research.

The medical research and training enterprise in the United States is complex in both its scope and implementation. Accordingly, adaptations to the associated workforce needs present particular challenges. This is particularly true for maintaining or expanding national needs for physician-scientists where training resource requirements and competitive transitional milestones are substantial. For the individual, these phenomena can produce financial burden, prolong the career trajectory, and significantly influence career pathways. Hence, when national data suggest that future medical research needs in a scientific area may be met in a less than optimal manner, strategies to expand research and training capacity must follow. This article defines such an exigency for research and training in nonneoplastic hematology and presents potential strategies for addressing these critical workforce needs. The considerations presented herein reflect a summary of the discussions presented at 2 workshops cosponsored by the National Heart, Lung, and Blood Institute and the American Society of Hematology.

Harnessing the Power of Integrated Mitochondrial Biology and Physiology: A Special Report on the NHLBI Mitochondria in Heart Diseases Initiative.

Mitochondrial biology is the sum of diverse phenomena from molecular profiles to physiological functions. A mechanistic understanding of mitochondria in disease development, and hence the future prospect of clinical translations, relies on a systems-level integration of expertise from multiple fields of investigation. Upon the successful conclusion of a recent National Institutes of Health, National Heart, Lung, and Blood Institute initiative on integrative mitochondrial biology in cardiovascular diseases, we reflect on the accomplishments made possible by this unique interdisciplinary collaboration effort and exciting new fronts on the study of these remarkable organelles.

Predicting Productivity Returns on Investment: Thirty Years of Peer Review, Grant Funding, and Publication of Highly Cited Papers at the National Heart, Lung, and Blood Institute.

There are conflicting data about the ability of peer review percentile rankings to predict grant productivity, as measured through publications and citations. To understand the nature of these apparent conflicting findings, we analyzed bibliometric outcomes of 6873 de novo cardiovascular R01 grants funded by the National Heart, Lung, and Blood Institute (NHLBI) between 1980 and 2011. Our outcomes focus on top-10% articles, meaning articles that were cited more often than 90% of other articles on the same topic, of the same type (eg, article, editorial), and published in the same year. The 6873 grants yielded 62 468 articles, of which 13 507 (or 22%) were top-10% articles. There was a modest association between better grant percentile ranking and number of top-10% articles. However, discrimination was poor (area under receiver operating characteristic curve [ROC], 0.52; 95% confidence interval, 0.51-0.53). Furthermore, better percentile ranking was also associated with higher annual and total inflation-adjusted grant budgets. There was no association between grant percentile ranking and grant outcome as assessed by number of top-10% articles per $million spent. Hence, the seemingly conflicting findings on peer review percentile ranking of grants and subsequent productivity largely reflect differing questions and outcomes. Taken together, these findings raise questions about how best National Institutes of Health (NIH) should use peer review assessments to make complex funding decisions.

The Congenital Heart Disease Genetic Network Study: rationale, design, and early results.

Congenital heart defects (CHD) are the leading cause of infant mortality among birth defects, and later morbidities and premature mortality remain problematic. Although genetic factors contribute significantly to cause CHD, specific genetic lesions are unknown for most patients. The National Heart, Lung, and Blood Institute-funded Pediatric Cardiac Genomics Consortium established the Congenital Heart Disease Genetic Network Study to investigate relationships between genetic factors, clinical features, and outcomes in CHD. The Pediatric Cardiac Genomics Consortium comprises 6 main and 4 satellite sites at which subjects are recruited, and medical data and biospecimens (blood, saliva, cardiovascular tissue) are collected. Core infrastructure includes an administrative/data-coordinating center, biorepository, data hub, and core laboratories (genotyping, whole-exome sequencing, candidate gene evaluation, and variant confirmation). Eligibility includes all forms of CHD. Annual follow-up is obtained for probands <1-year-old. Parents are enrolled whenever available. Enrollment from December 2010 to June 2012 comprised 3772 probands. One or both parents were enrolled for 72% of probands. Proband median age is 5.5 years. The one third enrolled at age <1 year are contacted annually for follow-up information. The distribution of CHD favors more complex lesions. Approximately, 11% of probands have a genetic diagnosis. Adequate DNA is available from 97% and 91% of blood and saliva samples, respectively. Genomic analyses of probands with heterotaxy, atrial septal defects, conotruncal, and left ventricular outflow tract obstructive lesions are underway. The scientific community's use of Pediatric Cardiac Genomics Consortium resources is welcome.

Funding mechanisms and program management at the National Heart, Lung, and Blood Institute: confronting new challenges and exploring new opportunities.

Over the past 8 years, the National Institutes of Health (NIH) budget appropriation has lost purchasing power, with erosion of the benefits of the doubling of the budget less than a decade ago. For the first time in 40 years, the NIH appropriation in fiscal year 2011 was 1% less than in the previous year. The National Heart, Lung, and Blood Institute (NHLBI) has been closely managing its funds to protect its core functions: support and conduct of research, and training of biomedical research scientists. Rigorous evaluations of funding mechanisms, management of clinical studies, set-aside programs and funding guidelines are designed to help the Institute, in consultation with its advisory council, to minimize the long-term impact of extreme resource limitations on the advance and conduct of science. This report describes some recent actions taken by the NHLBI to maximize support for investigator-initiated research, maintain a balanced portfolio, and provide as much support as possible for established and early-stage investigators.

Stakeholder Engagement in Late-Stage Translation Research and Implementation Science: Perspectives From the National Heart, Lung, and Blood Institute.

Stakeholder engagement is crucial for turning discovery into health. Although it is a highly effective approach for research in general, it is an essential component in late-stage translation research and implementation science in which the central objective is to accelerate the sustained uptake and integration of proven-effective interventions into routine clinical and public health practice. Where the stakeholder is an entire community, the term community engagement has often been used and has traditionally been defined as "the process of working collaboratively with groups of people who are affiliated by geographic proximity, special interests, or similar situations with respect to issues affecting their well-being." More recently, this definition has been expanded to specifically incorporate pre-study needs assessment, shared decision making about study themes and specific aims, data collection and analysis, interpretation and dissemination of research findings, and plans for scale-up and spread of research findings. In this article, the authors explore the scientific foundations of stakeholder engagement in biomedical research and public health practice. They highlight the strategic vision goals and objectives of the National Heart, Lung, and Blood Institute and the commitment to advance dissemination and implementation research and community-engaged participatory research. The authors conclude with comments on the stakeholder engagement efforts in the National Heart, Lung, and Blood Institute-funded TREIN/Hy-TREC consortium's work published in this issue of Global Heart and their perspectives on the challenges and opportunities as we chart the future together.

The National MDS Natural History Study: design of an integrated data and sample biorepository to promote research studies in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS), a spectrum of heterogeneous hematopoietic stem cell diseases, vary in clinical severity, response to therapy, and propensity toward progression to acute myeloid leukemia. These are acquired clonal disorders resulting from somatic mutations within the hematopoietic stem or progenitor cell population. Understanding the natural history and the risk of developing leukemia and other adverse outcomes is dependent on access to well-annotated biospecimens linked to robust clinical and molecular data. To facilitate the acquisition and distribution of MDS biospecimens to the wider scientific community and support scientific discovery in this disease, the National MDS Natural History study was initiated by the National Heart, Lung, and Blood Institute (NHLBI) and is being conducted in collaboration with community hospitals and academic medical centers supported by the National Cancer Institute (NCI). The study will recruit up to 2000 MDS patients or overlapping myeloproliferative neoplasms (MDS/MPN) and up to 500 cases of idiopathic cytopenia of undetermined significance (ICUS). The National MDS Natural History Study (NCT02775383) will offer the world's largest disease-focused tissue biobank linked to longitudinal clinical and molecular data in MDS. Here, we report on the study design features and describe the vanguard phase of 200 cases. The study assembles a comprehensive clinical database, quality of life results, laboratory data, histopathology slides and images, genetic information, hematopoietic and germline tissues representing high-quality biospecimens and data from diverse centers across the United States. These resources will be available to the scientific community for investigator-initiated research.

NHLBI step-by-step approach to adapting cardiovascular training and education curricula for diverse audiences.

Racial and ethnic minority communities need to be involved in developing health information to ensure its cultural appropriateness, improve its acceptability, and stimulate adoption of healthy behaviors. The National Heart, Lung, and Blood Institute at the National Institutes of Health adapted a heart-health curriculum for Latinos into culturally appropriate curricula for American Indians/Alaska Natives, African Americans, and Filipinos. Lessons learned from this process can assist public health practitioners interested in adapting science-based heart-health information into practical health education messages that meet the cultural and contextual needs of diverse groups.